Williams has played just three tournaments all season, losing in the final of the Australian Open and at Indian Wells.
With the world's dominant player missing for so much of the season, 16 different women have already lifted WTA titles this year, with Sloane Stephens, Victoria Azarenka and Angelique Kerber the only multiple winners.
That makes it hard to pick a winner for the tournament that starts this weekend, with Poland's Agnieszka Radwanska now the top seed, while five-time Grand Slam champion Maria Sharapova is still in the wilderness after failing a drugs test at Melbourne Park in January.
And the German is looking to build on her positive start to the European clay-court season in Madrid and Rome before the French Open next month.
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"I know I can play well on clay," said Kerber. "This is the attitude I'll take to Paris."
The faster conditions than a normal clay surface in Madrid due to the slight altitude of the Spanish capital could help Kerber even more.
Two-time champion Petra Kvitova returns to defend her crown at the Caja Magica and strongly believes the conditions favour her style.
"The balls really fly and I think that the players who are just pushing the ball don't really have a chance to finish the ball."
World number five Azarenka is the most in-form player on the Tour as the Belarusian arrives in Madrid on the back of a 14-match winning streak having won in Indian Wells and Miami, as well as helping her country relegate Russia in the World Group II in the Fed Cup earlier this month.
Home hopes are carried by Garbine Muguruza as the world number four hopes to become the first Spanish woman to win the Madrid Open.
However, Muguruza has had a disappointing season so far as she has failed to make it beyond the quarter-finals in seven tournaments.